Compound- and sex-specific medial prefrontal cortex rewiring after prenatal THC and CBD exposure

Abstract The growing perception of cannabinoids as benign has increased perinatal exposure to both Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), yet their long-term effects on prefrontal circuitry remain incompletely defined. Here we used whole-cell and field electrophysiology in adult mice (P100-140) of both sexes to compare how in utero exposure to THC or CBD (GD5-18) remodels layer-5 pyramidal neurons in the medial prefrontal cortex (mPFC). We quantified intrinsic excitability, excitatory and inhibitory synaptic transmission, the net E/I ratio, spontaneous excitatory and inhibitory currents kinetics, and canonical forms of synaptic plasticity (endocannabinoid-mediated LTD and NMDA-dependent LTP). Both cannabinoids shifted the adult mPFC toward a more pro-excitatory state: the E/I ratio was altered in a compound- and sex-dependent manner, and endocannabinoid-mediated LTD was abolished across groups. THC recapitulated previously reported deficits, producing male-specific increases in intrinsic excitability and accelerating excitatory current kinetics in females, demonstrating a conserved cross-species vulnerability of prefrontal circuits to gestational THC. CBD produced distinct signatures: female offspring showed marked increases in spontaneous excitatory event frequency and amplitude, indicating large-scale reorganization of excitatory and inhibitory inputs, while male offspring exhibited a selective and profound impairment of LTP. The combination of universal eLTD loss and CBD-specific LTP impairment in males yields a bidirectional loss of plasticity: an emergent synaptic rigidity in which circuits are unable to potentiate or depress effectively. Together, these convergent and divergent effects establish that prenatal exposure to THC and CBD produces lasting, sex-dependent rewiring of mPFC circuitry. Our results caution that the non-intoxicating profile of CBD does not preclude durable developmental impact and underscore the importance of considering both compound identity and sex when assessing the neurodevelopmental risks of perinatal cannabinoid exposure.